This proposal describes a program directed toward the total synthesis of leuconolide A3 and related 16-member ring macrolide antibiotics. The strategy involves the construction of three fragments. (Cl-C6, C7-C9, and Cl0-C15) and their combination by a l,4-addition of an organocuprate reagent to an unsaturated ester, a l,2-addition of an organolithium of organomagnesium reagent to an aldehyde, and finally lactonization. The major chiral centers are to be established using D-glucose as starting material for the Cl-C6 fragment. The flexibility of the outlined scheme will eventually permit the construction of the aglycones of several clinically useful antibiotics as well as analogs for biological evaluation.